Chelating Carbene Ligand Precursors and Their Use in the Synthesis of Metathesis Catalysts

ABSTRACT

Chelating ligand precursors for the preparation of olefin methathesis catalysts are disclosed. The resulting catalysts are air stable monomeric species capable of promoting various methathesis reactions efficiently, which can be recovered from the reaction mixture and reused. Internal olefin compounds, specifically beta-substituted styrenes, are used as ligand precursors. Compared to terminal olefin compounds such as unsubstituted styrenes, the beta-substituted styrenes are easier and less costly to prepare, and more stable since they are less prone to spontaneous polymerization. Methods of preparing chelating-carbene methathesis catalysts without the use of CuCl are disclosed. This eliminates the need for CuCl by replacing it with organic acids, mineral acids, mild oxidants or even water, resulting in high yields of Hoveyda-type methathesis catalysts. The invention provides an efficient method for preparing chelating-carbene metathesis catalysts by reacting a suitable ruthenium complex in high concentrations of the ligand precursors followed by crystallization from an organic solvent.

RELATED APPLICATIONS

This application is a continuation of pending U.S. patent applicationSer. No. 12/912,723, filed Oct. 26, 2010, which is a continuation ofU.S. patent application Ser. No. 12/333,125, filed Dec. 11, 2008, nowU.S. Pat. No. 7,820,843, which is a continuation of U.S. patentapplication Ser. No. 11/853,598, filed Sep. 11, 2007, now abandoned,which is a continuation of U.S. patent application Ser. No. 11/344,637,filed Jan. 31, 2006, now U.S. Pat. No. 7,268,242, which is acontinuation of U.S. patent application Ser. No. 10/665,734, filed Sep.16, 2003, now U.S. Pat. No. 7,026,495, which is a continuation of U.S.patent application Ser. No. 10/295,773, filed Nov. 15, 2002, now U.S.Pat. No. 6,620,955, which claims the benefit of U.S. ProvisionalApplication No. 60/334,781, filed Nov. 15, 2001. Each of theafore-mentioned applications and patents is incorporated by referenceherein in its' entirety.

BACKGROUND OF THE INVENTION

Well-defined transition metal carbene complexes have emerged as thecatalysts of choice for a wide variety of selective olefin metathesistransformations [F. Z. Dörwald, Metal Carbenes in Organic Synthesis;Wiley VCH, Weinheim, 1999]. These transformations include olefin crossmetathesis (CM), ring-opening metathesis (ROM), ring-opening metathesispolymerization (ROMP), ring-closing metathesis (RCM), and acyclic dienemetathesis (ADMET) polymerization [K. J. Ivin and J. C. Mol, OlefinMetathesis and Metathesis Polymerization; Academic Press, London, 1997].Of particular importance has been the development of ruthenium carbenecatalysts demonstrating high activity combined with unprecedentedfunctional group tolerance [T. M. Trnka and R. H. Grubbs, Acc. Chem.Res., 2001, 34, 18-29]. Olefin metathesis serves as a key reaction forthe development of a range of regioselective and stereoselectiveprocesses. These processes are important steps in the chemical synthesisof complex organic compounds and polymers and are becoming increasinglyimportant in industrial applications. [see for example Pederson andGrubbs U.S. Pat. No. 6,215,019].

An initial concern about using ruthenium olefin metathesis catalysts incommercial applications has been reactivity and catalyst lifetime. Theoriginal breakthrough ruthenium catalysts were primarily bisphosphinecomplexes of the general formula (PR₃)₂(X)₂Ru═CHR′ wherein X representsa halogen (e.g., Cl, Br, or I), R represents an alkyl, cycloalkyl, oraryl group (e.g., butyl, cyclohexyl, or phenyl), and R′ represents analkyl, alkenyl, or aryl group (e.g., methyl, CH═CMe₂, phenyl, etc.).Examples of these types of catalysts are described in U.S. Pat. Nos.5,312,940, 5,969,170 and 6,111,121. Though they enabled a considerablenumber of novel transformations to be accomplished, these bisphosphinecatalysts can exhibit lower activity than desired and, under certainconditions, can have limited lifetimes.

More recent developments of metathesis catalysts bearing a bulkyimidizolylidine ligand [Scholl et. al. Organic Letters 1999, 1, 953-956]such as 1,3-dimesitylimidazole-2-ylidenes (IMES) and1,3-dimesityl-4,5-dihydroimidazol-2-ylidenes (sIMES), in place of one ofthe phosphine ligands have led to greatly increased activity andstability. For example, unlike prior bisphosphine complexes, the variousimidizolyidine catalysts effect the efficient formation oftrisubstituted and tetrasubstituted olefins through catalyticmetathesis. Examples of these types of catalysts are described in PCTpublications WO 99/51344 and WO 00/71554. Further examples of thesynthesis and reactivity of some of these active ruthenium complexes arereported by A. Fürstner, L. Ackermann, B. Gabor, R. Goddard, C. W.Lehmann, R. Mynott, F. Stelzer, and O. R. Theil, Chem. Eur. J., 2001, 7,No. 15, 3236-3253; S. B. Gaber, J. S. Kingsbury, B. L. Gray, and A. H.Hoveyda, J. Am. Chem. Soc., 2000, 122, 8168-8179; Blackwell H. E.,O'Leary D. J., Chatterjee A. K., Washenfelder R. A., Bussmann D. A.,Grubbs R. H. J. Am. Chem. Soc. 2000, 122, 58-71; Chatterjee, A. K.,Morgan J. P., Scholl M., Grubbs R. H. J. Am. Chem. Soc. 2000, 122,3783-3784; Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J.;Hoveyda, A. H. J. Am. Chem. Soc. 1999, 121, 791-799; Harrity, J. P. A.;Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am. Chem. Soc. 1997,119, 1488-1489; and Harrity, J. P. A.; La, D. S.; Cefalo, D. R.; Visser,M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343-2351.

The improvements in catalyst activity and expansion of potentialsubstrates resulted in the ruthenium metathesis systems becomingattractive candidates for use in industrial scale processes. Inparticular, many of the targeted products of olefin metathesis areuseful as intermediates in flavors and fragrances, pharmaceuticals andother fine chemicals. Thus, a second major concern has involvedruthenium residues that may be present in the products produced bymetathesis. To address this issue, several catalyst removal techniqueshave been developed [Maynard and Grubbs in Tetrahedron Letters 1999, 40,4137-4140; L. A. Paquette, J. D. Schloss, I. Efremov, F. Fabris, F.Gallou, J. Mendez-Andino and J. Yang in Org. Letters 2000, 2,1259-1261;and Y. M. Ahn; K. Yang, and G. I. Georg in Org. Letters 2001, 3, 1411],including that described by Pederson and Grubbs [Pederson and Grubbs,U.S. Pat. No. 6,215,049] which is still the most amenable to large scalereactions. Ruthenium metathesis catalysts with a wide range ofreactivity and that could be easily removed from the product were nowavailable.

Further progress towards catalyst selectivity, stability, and removalhas been recently published by Hoveyda and others [Kingsbury, J. S.;Harrity, J. P. A.; Bonitatebus, P. J.; Hoveyda, A. H. J. Am. Chem. Soc.1999, 121, 791-799] with the demonstration of new, readily recyclablecatalyst systems containing chelating carbene species (Scheme 1) thatare exceptionally stable and can even be purified by columnchromatography in air. For example, the tricyclohexylphosphine-ligatedvariant, Catalyst 601 (Scheme 1), can be recovered in high yield fromthe reaction mixture by simple filtration through silica. Hoyveda andcoworkers also demonstrated [Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J.Organometallic Chemistry 2001, 624, 327-332] that by replacement of thephosphine with the sIMES ligand, Catalyst 627 (Scheme 1) activelypromotes the cross-metathesis of acrylonitrile and terminal olefins inmoderate to excellent yields (20% to 91%) with a cis to trans olefinratios that range from 2:1 to over 9:1. Related chelating carbenecatalysts are described in US Patent Application Publication No.2002/0107138 and U.S. Pat. No. 6,306,987.

Prior methods used to make these chelating carbene complexes includetreating (Ph₃P)₃RuCl₂ with the appropriate diazo species at lowtemperatures or treatment of a metathesis-active metal carbene complexwith the parent styrene in the presence of CuCl followed by columnchromatography (Scheme 2). While both of these methods yield the desiredcompound, they are difficult to scale up. Maintaining very lowtemperatures on larger reaction vessels requires expensive equipment,and diazo species are prone to violent decomposition under certainconditions. Using the o-isopropoxy styrene/CuCl route is also notamenable to large scale due to the requirement to purify the product bycolumn chromatography. A further shortcoming includes the use of theWittig reaction to yield the key styrene intermediate. Wittig reactionsare not convenient on a commercial scale because of the high costs ofthe reagents and the by-product, triphenylphosphine oxide, produces anexcessive mass of waste. Alternatives to Wittig reactions would includeHeck, Stille or Suzuki coupling of vinyl trialkyltin, vinyl triflates orvinyl borate; respectively, to a halo-phenol substrate. These startingmaterials are generally expensive, and the reactions with trialkyl tinreagents involve toxic compounds which require special waste disposalprocedures. Finally the styrene itself is prone to polymerization undersome of the conditions required to make the “Hoveyda-type” catalysts.Therefore, there is a need for an efficient and economical synthesis tochelating carbene type ruthenium metathesis catalysts in largerquantities.

The present invention describes efficient and versatile routes to usefuland valuable Hoveyda-type catalysts with chelating phenyl carbeneligands while eliminating expensive and toxic reagents. The presentinvention describes the synthesis of substituted olefins that areprecursors to catalyst complexes and their use as reagents to prepareolefin metathesis catalysts with chelating carbene ligands.

SUMMARY OF THE INVENTION

The present invention comprises methods for the use of novel chelatingligand precursors for the preparation of olefin metathesis catalysts.The resulting catalysts comprise monomeric species which are air stable,are capable of promoting various forms of metathesis reactions in ahighly efficient manner, and can be recovered from the reaction mixtureand reused.

One embodiment of the present invention is the use of internal olefincompounds, specifically beta-substituted styrenes, as ligand precursorsinstead of terminal olefin compounds such as unsubstituted styrenes(Scheme 3). Although internal olefins tend to be less reactive thanterminal olefins, we have surprisingly found that the beta-substitutedstyrenes are sufficiently reactive to efficiently produce the desiredcatalyst complexes. Compared with the styrene compounds, thebeta-substituted styrenes are much easier and less costly to prepare inlarge quantities and are more stable in storage and use since they areless prone than terminal styrenes to spontaneous polymerization.

Another embodiment of the present invention are methods of preparingchelating-carbene metathesis catalysts without the use of CuCl aspreviously required. In previous reports, CuCl was used to sequesterphosphine ligands which shifts the equilibrium of metathesis reactionsto product formation. The use of CuCl in large scale synthesis isproblematic in that the resulting metathesis catalyst must be purifiedby chromatography before recrystallization, requiring large volumes ofsilica and solvent [Kingsbury et. al. J. Am. Chem. Soc. 1999, 121,791-799]. The present invention eliminates the need for CuCl byreplacing it with organic acids, mineral acids, mild oxidants or evenwater, resulting in high yields of Hoveyda-type metathesis catalysts.The phosphine byproduct is removed by an aqueous wash or filtration,thereby eliminating the chromatography step and allowing catalysts to bereadily isolated by crystallization from common organic solvents.

A further embodiment of the present invention is an efficient method forpreparing chelating-carbene metathesis catalysts by reacting a suitableruthenium complex in high concentrations of the novel ligand precursorsfollowed by crystallization from an organic solvent. For example, inthis manner Catalyst 601 can be simply isolated by filtering a hexanesolution of the reaction mixture resulting from the reaction of neatligand precursor and a ruthenium carbene complex. By using thebeta-substituted styrene derivatives, the excess, unreacted ligand isrecoverable from such reaction mixtures and can be reused. This isdifficult with the parent styrenes due to the propensity of thosematerials to polymerize under reaction and workup conditions.

DETAILED DESCRIPTION OF THE INVENTION

The present invention describes the synthesis of “Hoveyda-type”chelating carbene metathesis catalysts from the cross metathesis ofnovel ligand precursors and metal carbene complexes. Although anymetathesis-active metal carbene complex is suitable for use in thepresent invention, preferred metal complexes include the Grubbs-typecompounds described in U.S. Pat. Nos. 5,312,940, 5,969,170, 6,111,121and 6,426,419 and PCT publications WO 99/51344 and WO 00/71554. Thesecomplexes have the general formula X¹X²L¹L²M=CR¹R², wherein X¹and X² areeach, independently, any anionic ligand; L¹ and L² are each,independently, any neutral electron donor ligand; M is ruthenium orosmium; and R¹ and R² are each, independently, hydrogen or a groupselected from the group consisting of alkyl, alkenyl, alkynyl, aryl,alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkoxycarbonyl, alkylthio,alkylsulfonyl, alkylsulfinyl and trialkylsilyl, any of which may beoptionally substituted with a functional group selected from the groupconsisting of halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl,alkoxy, alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl, alkylamino,alkylthio, alkylsulfonyl, nitrile, nitro, alkylsulfinyl, trihaloalkyl,perfluoroalkyl, carboxylic acid, ketone, aldehyde, nitrate, cyano,isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide,disulfide, sulfonate, carbamate, silane, siloxane, phosphine, phosphate,or borate.

The ligand precursors of the present invention are functionalizedbeta-substituted styrene compounds, which may be conveniently preparedby the isomerization of functionalized allylbenzenes, with the structureshown in Scheme 4.

wherein:

Y is a heteroatom such as oxygen (O), sulfur (S), nitrogen (N), orphosphorus (P);Z is a group selected from hydrogen, alkyl, aryl,functionalized alkyl, functionalized aryl where the functional group(s)may independently be one or more or the following: alkoxy, aryloxy,halogen, carboxylic add, ketone, aldehyde, nitrate, cyano, isocyanate,hydroxyl, ester, ether, amine, imine, amide, sulfide, disulfide,carbamate, silane, siloxane, phosphine, phosphate, or borate.

n is 1, in the case of a divalent heteroatom such as O or S, or 2, inthe case of a trivalent heteroatom such as N or P;

R³ and R⁴ are independently selected from the group consisting ofhydrogen, C₁-C₂₀ alkyl, C₂-C₂₀ alkenyl, C₂-C₂₀ alkynyl, C₁-C₂₀substituted aryl, C₁-C₂₀ functionalized alkyl, C₂-C₂₀ functionalizedalkeneyl, C₂-C₂₀ functionalized alkenyl, or C₁-C₂₀ functionalizedsubstituted aryl where the functional group(s) may independently be oneor more or the following: alkoxy, aryloxy, halogen, carboxylic acid,ketone, aldehyde, nitrate, cyano, isocyanate, hydroxyl, ester, ether,amine, imine, amide, sulfide, disulfide, carbamate, silane, siloxane,phosphine, phosphate, or borate;

R⁵, R⁶, R⁷, and R⁸ are each, independently, selected from the groupconsisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl,alkylamino, alkylthio, alkylsulfonyl, nitrile, nitro, alkylsulfinyl,trihaloalkyl, perfluoroalkyl, carboxylic acid, ketone, aldehyde,nitrate, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide,sulfide, disulfide, sulfonate, carbamate, silane, siloxane, phosphine,phosphate, or borate. Additionally, any two or more of R⁵, R⁶, R⁷,and/or R⁸ may be independently connected through hydrocarbon orfunctionalized hydrocarbon groups forming aliphatic or aromatic rings.Furthermore, one who is skilled in the art will recognize that R⁸ shouldbe chosen such that its steric bulk or chemical functionality does notinterfere with the cross-metathesis reaction between the ligandprecursor and the metal carbene complex. Any one or more of R⁵, R⁶, R⁷,and R⁸ (but preferably any of R⁵, R⁶, and R⁷) may be a linker to a solidsupport such as silica, swellable polymeric resins, dendritic polymers,and the like as, for example, described in US Patent ApplicationPublication No. 2002/0107138 or by Grela (et al.) in TetrahedronLetters, 2002, 43, 9055-9059 for terminal-styrene ligand precursors.

Preferred ligand precursors are beta-methyl styrenes wherein Y is oxygenor sulfur; n is 1; Z is alkyl, aryl or trialkylsilyl; and R³ and R⁴ areboth hydrogen. Particularly preferred ligand precursors arealkoxy-substituted beta-methyl styrenes wherein Y is oxygen; n is 1; Zis methyl, isopropyl, sec-butyl, t-butyl, neopentyl, benzyl, phenyl ortrimethylsilyl; and R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are all hydrogen. Examplesof particularly preferred ligand precursors of these types include2-methoxy-β-methylstyrene, 2-isopropoxy-β-methylstyrene and2-isopropoxy-3-phenyl-β-methylstyrene:

The precursor compounds for chelating ligands are easily prepared inhigh yields from commercially available starting materials. Treatment ofallyl aryl compounds with an isomerization catalyst cleanly migrates thedouble bond one carbon closer to the aryl ring forming abeta-substituted styrenic olefin (Scheme 4). We have found that(PPh₃)₃RuCl₂ is a preferred, highly active isomerization catalyst thatis effective at amounts ranging from about 0.001 to 20 mole percentrelative to the allyl aryl compound. It is preferable to isomerize theallylphenol compounds prior to further functionalization, since thehydroxy protons serve to activate the catalyst and the reactions cantherefore be run neat. For other compounds without their own proticsource, it is necessary to add an alcohol or other proton source toinitiate the isomerization catalysis. From the structures shown inScheme 4, one skilled in the art can appreciate the diversity ofsubstitution on the aromatic system that can be achieved. This allowsthe ligand to be fine-tuned for specific applications. For the casewhere Y is oxygen, a wide variety of allyl phenol starting materials areeasily produced by the Claisen rearrangement (Scheme 5) of allylic arylethers [March's Advanced Organic Chemistry; 5^(th) Edition, Eds. M. B.Smith and J. March; John Wiley and Sons, New York, N.Y. 2001, pp.1449-1452]. Similar rearrangements are operative for the case where Y isnitrogen, although more forcing conditions are typically required.

The above described ligand precursors can be used to prepare metathesiscatalysts with a chelating carbene group. In the most basic practice ofthe present invention, as with the parent styrenes, it is possible tomix a metathesis active metal carbene complex with the ligand precursorin a suitable solvent to effect the transformation. Preferred solventstypically include, but are not limited to, chlorinated solvents (such asmethylene chloride, dichloroethane, chlorobenzene, anddichlorobenzenes), ethereal solvents (such as tetrahydrofuran ordioxane), aromatic solvents (such as benzene, toluene, or xylenes), andhydrocarbon solvents (such as hexanes, heptane, and petroleum distillatefractions). In general, at least one equivalent, and preferably anexcess amount, of the ligand precursor is utilized. Depending upon thereactivity of the metathesis-active metal carbene complex, the reactionmay proceed at room temperature, or even lower, or may need to beheated. As the progress of these reactions can be conveniently monitoredby a variety of techniques including thin-layer chromatography (TLC),those skilled in the art can readily ascertain the appropriateconditions of time and temperature to achieve high conversions to thedesired chelating carbene complexes.

In general, these reactions proceed more slowly and/or require somewhathigher reaction temperatures than comparable reactions with terminalstyrenes. In order to increase the reaction rates and achieve higherconversion, high ratios of ligand precursor to metal carbene complex canbe utilized. In fact, in the practice of the present invention, thereaction can be performed using neat ligand precursor as the solvent. Ingeneral, five to ten mole-equivalents of ligand precursor will givereasonable reaction rates and high conversions. This approach cannot beutilized with the terminal styrene ligand precursors due to theirpropensity to spontaneously polymerize under the reaction conditions.Upon completion of the reaction, the ligand precursor can be distilledoff of the reaction mixture and the chelating carbene productrecrystallized from an appropriate solvent. Alternatively, the chelatingcarbene product can be precipitated by the addition of an appropriatenonsolvent and the unreacted ligand precursor recovered by distillationof the mother liquor. The beta-substituted styrene compounds aresufficiently robust so that high recoveries can be achieved by thesemethodologies, which would not be practical with the easily polymerizedterminal styrenes.

In general, treatment of one mass equivalent of a ruthenium carbenecomplex with between 1 and 20 mass equivalents of ligand precursor inthe presence of an optional co-solvent (generally between about 1-20mass equivalents relative to the ruthenium complex) yields a thickmixture that gradually looses viscosity during the course of thereaction. Optionally the mixture can be heated or cooled. The mixturemay also be exposed to a static or dynamic vacuum. The reaction ispreferably conducted under an inert atmosphere but may be conducted inair unless the metal carbene complex is particularly air-sensitive.After 3-120 hours of stirring, the reaction is usually complete and theproduct may be isolated as described above.

A complementary method for increasing reaction rates and conversionutilizes an additive to sequester the ligand that is displaced from themetal carbene complex during the course of the reaction. When thedisplaced ligand is a phosphine ligand, as is typical, the sequesteringagent that has been commonly used in cuprous cloride (CuCl), althoughthis is difficult to separate from the product without usingchromatograhy which is impractical at large scale. Suprisingly, we havefound that replacement of the CuCl with mineral acids, organic acids ormild oxidants in the presence of the ligand precursors of the presentinvention is also very effective. Treatment of ruthenium carbenecomplexes with between 1 to 10 equivalents of ligand precursor andbetween 0.1 to 10 equivalents acid or mild oxidant yields the newcatalyst containing the chelating carbene moity. After the reaction iscomplete, the displaced ligand and the sequestering agent can be readilyremoved from the mixture by extraction into water. The product can thenbe simply crystallized from the resulting solution in organic solventsin very high yield, eliminating the need for column chromatography.Preferred sequestering agents include hydrochloric acid, solutions ofhydrogen chloride in ethereal solvents (such as diethyl ether,tetrahydrofuran, or dioxane), gaseous hydrogen chloride dissolved in thereaction mixture, glacial acetic acid, bleach, and dissolved oxygen.Water can be utilized as a sequestering agent for particularly basicligands such as tricyclohexylphosphine (TCHP or PCy₃). The use ofsequestering agents is particularly perferred when using very robustmetal carbene complexes such as those containing IMES or sIMES ligands.When using less robust complexes such as ruthenium carbenes ligated withtwo phosphine ligands, greater care is needed and it is desirable toutilize the mildest sequestering agents or to slowly add thesequestering agents over the course of the reaction.

EXAMPLES Example 1 Synthesis of o-hydroxy beta-methyl styrene [1] from2-allylphenol

To a dry 100 mL round-bottom flask containing a magnetic stirbar wasadded 25 g (186 mmol) of 2-allylphenol (Aldrich). The flask was spargedwith argon for 30 minutes, followed by the addition of 71 mg (0.05 mol%)of (PPh₃)₂Cl₂Ru, a highly effective double-bond isomerization catalyst,and then heated to 70° C. for 17.5 hours. GC analysis* indicated >99%conversion of 2-allyl phenol to o-hydroxy beta-methyl styrene. GCresults show ortho-hydroxy beta-methyl styrene R^(t) 8.51 minutes andR^(t) 11.13 minutes (Z and E isomers), and 2-allylphenol R^(t) 8.86minutes. The catalyst was removed with tris-hydroxymethyl phosphine(THP), as previously described by Pederson and Grubbs [U.S. Pat. No.6,219,019], to yield 25 g, quantitative yield. Isomeric ratio of E:Zisomers was 45:55. *GC Analysis: HP 5890 GC with DB 225 capillary GCcolumn (30 m×0.25 mm ID×0.25 um film thickness) Head pressure 15 psi,FID detection. Method: 100° C. for 1 minute then 10° C/minute to 210° C.for 6 minutes.

Example 2 Synthesis of ortho-Isopropoxy beta-Methyl Styrene [2]

Protection of an aromatic hydroxyl group with isopropyl was as describedby T. Sala and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 2593,(1979). To a dry 500 mL round-bottom flask containng a magnetic stirbarwas added 50 g (373 mmol) of ortho-hydroxy beta-methyl styrene, 57.3 g(466 mmol) isopropyl bromide, 300 mL of anhydrous dimethylformamide(DMF), and 64 g (466 mmol) K₂CO₃. The heterogeneous mixture was warmedto 60° C. After 9 hours the reaction was 57% converted, 30 g (244 mmol)isopropyl bromide and 32 g (232 mmol) of K₂CO₃ was added, and stirringwas continued. After 48 hours, GC analysis indicated >98% conversion toortho-isopropoxy beta-methyl styrene. GC results: ortho-hydroxybeta-methyl styrene R^(t) 8.51 minutes and R^(t) 11.13 minutes (Z and Eisomers), ortho-isopropoxy beta-methyl styrene R^(t) 7.35 minutes(Z-isomer) and R^(t) 8.30 minutes (E-isomer).

The reaction was cooled to room temperature and 200 mL of water and 100mL of tertiary-butyl methyl ether (TBME) were added and mixed. Thephases were separated and the aqueous phase was washed with another 100ml of TBME. The organic phases were combined and washed with 2×100 mL ofwater, dried with anhydrous sodium sulfate, filtered and concentratedunder reduced pressure to yield crude ortho-isopropoxy beta-methylstyrene. Vacuum distillation (Bpt_(1.0) 60° C. to 65° C.) yielded 61.3 g(348 mmol) or 93% isolated yield.

¹H NMR (300 MHz) CDCl₃ δ: 7.8 (d, 1H aromatic), 7.5 (m, 1H, aromatic),6.90 (bt, 2H, aromatic), 6.4 (dd, 1H, Ph—CH═CH), 6.0 (m, 1H,Ph—CH═CHCH₃), 4.64 (m, 1H, CH(CH₃)₂), 1.35 (J 6.3 Hz, 6H, CH(CH ₃)₂).¹³C NMR (75 MHz) CDCl₃ δ: 130.23, 127.68, 127.52, 126.36, 125.99,125.71, 125.53, 120.59, 119.92, 114.08, 113.96, 70.58, 22.298, 19.09,14.87.

Example 3 Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene[2]: Synthesis of ortho-Isopropoxy Salicylaldehyde [3]

Similar to the procedure of Example 2, 6.5 g (53.2 mmol) ofsalicylaldehyde, 100 mL of anhydrous DMF, 6.5 g of K₂CO₃, and 10 g ofisopropyl bromide (81.3 mmol) were added to a dry 250 mL round-bottomflask containing a magnetic stirbar. The heterogeneous mixture wasstirred with heating to 60° C. for 24 hours when GC analysis indicatedcomplete conversion to o-isopropoxy salicylaldehyde. Water 100 mL wasadded and the organics were washed with 2×100 mL of TBME, the TBMEphases were combined and washed with 2×50 mL water, dried with anhydroussodium sulfate, filtered and concentrated to yield [3] (8.3 g, 95%yield). Salicylaldehyde R^(t) 6.473 minutes, ortho-isopropoxysalicylaldehyde R^(t) 10.648 minutes. ¹H NMR (300 MHz) CDCl₃ δ: 10.46(CHO), 7.8 (d, 1H aromatic), 7.5 (m, 1H, aromatic), 6.90 (t, 2H,aromatic), 4.64 (m, 1H, CH(CH₃)₂), 1.35 (J 6.3 Hz, 6H, CH(CH ₃)₂).

Example 4 Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene[2]: Synthesis of ortho-Isopropoxy (2′-Hydroxypropyl) Benzene [4]

To a 50 mL round-bottom flask was added 1 g (7.0 mmol) of [3] and 25 mLof anhydrous tetrahydrofuran (THF). The flask was sparged with Argonwhile cooling to −15° C. over 15 minutes. Ethyl magnesium chloride (3 mLof 3 M in ether) was added drop wise over 10 minutes. The reaction waswarmed to room temperature and quenched with water-saturated ammoniumchloride. GC analysis indicated >99% conversion to ortho-isopropoxy(2′-hydroxypropyl)benzene with R^(t)=10.969 minutes (4.1%) and 11.374minutes (95.9%), E and Z isomers. The product was isolated by usualmethods to yield [4] (1.4 g, quantitative yield). This product was usedin the next reaction without further purification.

Example 5 Alternative Synthesis of ortho-Isopropoxy beta-Methyl Styrene[2]

To a 250 mL round-bottom flask was added 1.4 g (7.0 mmol) of [4], 100 mLof anhydrous toluene, and 100 mg of p-toluene sulfonic acid. The mixturewas heated to 90° C. for 90 minutes when GC analysis indicated completeconversion to [2] with an isomeric ratio of E:Z isomers of 97:3. ¹H NMRand ¹³C NMR were in agreement with previously synthesized material.

Example 6 Synthesis of [(sIMES)(o-isopropoxyphenylmethylene)RutheniumDichloride] [6] from (sIMES)(PCy₃)Cl₂Ru═CHPh [5] and CuCl

To a dry 100 mL round-bottom flask containing a magnetic stirbar, underargon, was added 1.79 g (2.1 mmol, 1.0 equiv) [5], CuCl (521 mg, 5.28mmol, 2.51 equiv), and 25 mL of anhydrous CH₂Cl₂. Ligand precursor [2](403 mg, 2.1 mmol, 1.0 equiv) was added to the reddish solution in 20 mLof CH₂Cl₂ at room temperature. A reflux condenser was added and themixture was heated for 70 minutes, under argon. The crude product wasconcentrated and loaded onto silica gel and eluted with 2:1pentane:CH₂Cl₂ then 1:1 pentane:CH₂Cl₂to remove a dark green band. Thecolumn was washed with CH₂Cl₂, then Et₂O. The green and yellow bandswere combined and concentrated under reduced pressure to yield a darkgreen solid. The solvents are removed under reduced pressure and thesolid was crystallized from hexane to yield 1.07 g (1.70 mmol, 85%) of[6]. ¹H NMR (300 MHz, CDCl₃) δ: 16.56 (s, 1H, Ru═CHAr), 7.48 (m, 1H,aromatic CH), 7.07 (s, 4H, mesityl aromatic CH), 6.93 (dd, J=7.4 Hz, 1.6Hz, 1H, aromatic CH), 6.85 (dd, J=7.4 Hz, 1H, aromatic CH), 6.79 (d,J=8.6 Hz, 1H, aromatic CH) 4.90 (septet, J=6.3 Hz, 1H,(CH₃)₂CHOAr), 4.18(s, 4H, N(CH₂)₂N), 2.48 (s, 12H, mesityl o-CH₃), 2.40 (s, 6H, mesitylp-CH₃), 1.27 (d, J=5.9 Hz, 6H, (CH ₃)₂CHOAr. ¹³C NMR (75 MHz, CDCl₃) δ:296.8 (q, J=61.5 Hz), 211.1, 152.0, 145.1, 145.09, 138.61, 129.4 (d,^(J)NC 3.9 Hz), 129.3, 129.2, 122.6, 122.1, 122.8, 74.9 (d, ^(J)OC 10.7Hz), 51.4, 30.9, 25.9, 21.01.

Example 7 Synthesis of [6] from [5] and Bleach

To a dry 100 mL round-bottom flask containing a magnetic stirbar wasadded 1.79 g (2.1 mmol, 1.0 equiv) of [5], 10 mL of household bleach(i.e., aqueous sodium hypochlorite), and 25 mL of CH₂Cl₂. Ligandprecursor [2] (403 mg, 2.1 mmol, 1.0 equiv) was added to the reddishsolution in 20 mL of CH₂Cl₂ at room temperature. A reflux condenser wasadded and the mixture was heated for 4 hours. The organic phase waswashed with water, isolated, neutralized, dried, filtered andconcentrated under reduced pressure to yield a green solid.Crystallization from pentane yielded 43% of [6] of acceptable purity asindicated by NMR spectral analysis.

Example 8 Synthesis of [6] from [5] and Ethereal HCl

To a dry 100 mL round-bottom flask containing a magnetic stirbar wasadded 1.79 g (2.1 mmol, 1.0 equiv) of [5], 25 mL of CH₂Cl₂, and 2.4 mLof ethereal HCl (2.0 M, 2.0 equiv). Ligand precursor [2] (420 mg, 2.4mmol, 1.14 equiv) was added to the reddish solution in 20 mL of CH₂Cl₂at room temperature. A reflux condenser was added and the mixture washeated for 1 hour. The organic phase was washed with 2×25 mL water,dried with anhydrous sodium sulfate, filtered and concentrated underreduced pressure to yield a green solid. Crystallization fromCH₂Cl₂/hexane yielded [6] (1.03 g, 78% yield) as indicated by NMRspectral analysis.

Example 9 Synthesis of [(PCy₃)(o-isoproxyphenylmethylene)RutheniumDichloride] [8] from (PCy₃)₂Cl₂Ru═CHPh [7]

Ruthenium complex [7] (270 g, 0.32 moles) was charged into a 2L 3-neckroundbottom flask. Ligand precursor [2] (505 g, 2.8 moles) was thenadded, and one neck of the flask was fitted with a gas adapter; anotherwith a stopper and the third with a distillation head and receiverflask. The flask was placed under vacuum and slowly heated to 80° C. Themixture was maintained at between 65° C. and 70° C. under vacuum for 24hours. The temperature was raised to 80° C. and the remaining ligandprecursor was distilled away. The vacuum was broken and hexanes (1 L)was added to the flask. The reaction mixture was stirred for severalminutes then filtered. The solids were washed with warm hexanes(3×100mL) yielding [8] (96.2 g, 49% yield) as indicated by NMR spectralanalysis.

Example 10 Synthesis of [8] from (PCy₃)₂Cl₂Ru═CH—CH═C(CH₃)₂ [9]

Ruthenium complex [9] (48 g, 0.059 moles) was charged to a 1Lroundbottom flask and ligand precursor [2] was charged along withtoluene (400 g). A reflux condenser was attached to the flask and keptat 15° C. The mixture was warmed to 70° C. under vacuum for 12 hours.The condenser was warmed to 45° C. and the toluene was removed in vacuo.The mixture was then heated to 80° C. for 48 hours under a staticvacuum. A distillation head was attached to the flask and the remainingligand precursor distilled away in vacuo. 500 mL of hexanes was added tothe flask and the mixture was allowed to cool to room temperature withmixing. The mixture was filtered and the solids washed with hexanes (100mL) yielding 16.7 g (46% yield) of [8] as indicated by NMR spectralanalysis.

Example 11 Synthesis of [8] from [9] with Hydrochloric Acid

A mixture of methylene chloride (200 g) and ligand precursor [2] (200 g,1.136 moles) was charged into a roundbottom flask, warmed to 40° C., anddegassed by sparging with nitrogen gas. Ruthenium complex [9] (100 g,0.125 moles) was then added to the mixture against a nitrogen sparge.Hydrochloric acid (6N, 20 mL, 0.120 moles) was added slowly dropwisethrough an addition funnel over a period of three hours to the stirredmixture, which was maintained at 40° C. under nitrogen. After stirringfor an additional hour at 40° C., analysis by thin-layer chromatography(TLC) indicated only partial conversion. The mixture was then stirredfor an additional two hours at 50° C. and 1 hour at 60° C. until TLCsuggested nearly complete conversion. An additional 5 mL of 6Nhydrochloric acid was then added and the mixture stirred for two hoursto assure completion. While still warm, 100 mL of methanol was added,and the resulting mixture poured into 1,400 mL of methanol toprecipitate the product. The mixture was filtered and the solids washedand dried to yield 47.5 g (63% yield) of [8] as indicated by TLCanalysis.

Example 12 Synthesis of [8] from [9] with Water

A mixture of toluene (200 mL), ligand precursor [2] (100 g, 0.568moles), ruthenium complex [9] (49 g, 0.061 moles) and water (100 mL) wascharged into a roundbottom flask, sparged with nitrogen, and vigorouslystirred overnight at 80° C. Analysis by TLC indicated nearly completeconversion. Hydrochloric acid (6N, 10 mL) was then added and the mixturestirred for several minutes to assure completion. The aqueous layer wasremoved and 400 mL of methanol added to precipitate the product. Afterstirring overnight, the mixture was filtered and the solids washed withmethanol (50 mL), acetone (50 mL) and hexanes (50 mL) and dried to yield19 g (52% yield) of [8].

Example 13 Synthesis of [6] from [5] and Hydrochloric Acid in THF

Ligand precursor [2] (5.28 g, 0.030 mole) and 50 mL of a mixture of 1part concentrated hydrochloric acid in 5 parts tetrahydrofuran wereadded to a dry 500 mL round-bottom flask containing a magnetic stirbar.The mixture was degassed for ten minutes with a nitrogen sparge before10 g (0.012 mole) of [5] was added. The reaction mixture was then heatedto 60° C. for two hours when TLC analysis indicated that conversion wascomplete. After cooling to room temperature, the product precipitated,was collected by filtration, and washed with methanol to yield 4.33 g of[6] (59% yield). The filtrates were combined and refiltered to yield asecond crop of 1.07 g of [6], giving an overall yield of 73%.

Example 14 Synthesis of [6] from [5] and Hydrochloric Acid in THF

Ligand precursor [2] (2.64 g, 0.015 mole) and 30 mL of a mixture of 1part concentrated hydrochloric acid in 5 parts tetrahydrofuran wereadded to a dry round-bottom flask containing a magnetic stirbar. Themixture was degassed for ten minutes with a nitrogen sparge before 10 g(0.012 mole) of [5] was added. The reaction mixture was then heated to60° C. for two hours when TLC analysis indicated that conversion wascomplete. After cooling to room temperature, 30 mL of distilled waterwas added to help precipitate the product, which was collected byfiltration and washed with methanol to yield 5.37 g of [6] (73% yield).

Example 15 Synthesis of [6] from [5] and Gaseous Hydrogen Chloride

Ligand precursor [2] (84 g, 0.477 mole), [5] (161 g, 0.190 mole), and1.6 L of methylene chloride were added to a dry roundbottom flaskcontaining a magnetic stirbar and degassed with a nitrogen sparge. Dryhydrogen chloride gas was then bubbled through the mixture forapproximately ten seconds. After stirring for two hours, hydrogenchloride gas was again bubbled through the mixture for approximately tenseconds. After a total of five hours of stirring, TLC analysis indicatescomplete conversion. The reaction mixture was concentrated by rotaryevaporation before 500 mL of methanol was added to precipitate theproduct, which was isolated by filtration and washed twice with 100 mLof methanol to yield 97.5 g (82%) of [6].

Example 16 One-Pot Synthesis of [8] fromDichloro(1,5-cyclooctadiene)ruthenium

Dichloro(1,5-cyclooctadiene)ruthenium (4.0 g, 0.014 moles),tricyclohexylphosphine (8.4 g, 0.030 moles), degassed triethylamine (2mL), and degassed sec-butanol (60 mL) were combined in a pressure bottleunder argon. The pressure bottle was purged with hydrogen gas,pressurized to 60 psi, and the mixture heated to 80° C. for 18 hours(the bottle was repressurized as needed to maintain 60 psi hydrogen).The reaction mixture was then allowed to cool down and the hydrogen gaswas vented off. Degassed methanol (60 mL) was added to the orange slurryand the filtrate decanted off via stick filtration under argon to leavean orange solid in the bottle, which was washed with degassed methanol(60 mL). Degassed toluene (60 mL) was added to the orange solid and theorange slurry cooled to 0° C. Degassed 3-chloro-3-methyl-1-butyne (1.7mL, 0.015 moles) was added dropwise via syringe at 0° C. The orangeslurry progressively turned to a maroon slurry, while gas bubbled away.The mixture was stirred at room temperature for 2 hours after additionwas complete. Ligand precursor [2] (18 g, 0.102 moles) was then chargedand the mixture was heated to 80 ° C. and sparged with argon for 3 days(degassed toluene was added as needed). The brown slurry was allowed tocool to room temperature and a mixture of 30 mL methanol and 10 mL ofconcentrated hydrochloric acid was added in air with mixing. Afterstirring for 15 minutes at room temperature, the two phases were allowedto separate and the methanol phase was decanted off. Trituration withmethanol (2×50 mL) gave a solid, which was collected on a frit andwashed with more methanol (2×20 mL). The brown solid was then washedwith hexanes (2×20 mL) and dried to give [8] (5.1 g, 0.085 moles) in 61%yield.

1. A chelating carbene complex of the formula:

wherein X¹ and X² are each, independently, any anionic ligand; L¹ is anyneutral electron donor, and wherein any of two or three of X¹, X², andL¹ may form a multidentate ligand; M is ruthenium or osmium; R⁵, R⁶, R⁷,and R⁸ are each, independently, selected from the group consisting ofhydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy,alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl, alkylamino, alkylthio,alkylsulfonyl, nitrile, nitro, alkylsulfinyl, trihaloalkyl,perfluoroalkyl, carboxylic acid, ketone, aldehyde, nitrate, cyano,isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide,disulfide, sulfonate, carbamate, silane, siloxane, phosphine, phosphate,and borate, wherein any two of R⁵, R⁶, R⁷, and R⁸ may be independentlyconnected through hydrocarbon or functionalized hydrocarbon groupsforming an aliphatic or aromatic ring; Y is a heteroatom selected fromoxygen (O), sulfur (S), nitrogen (N), or phosphorus (P); and Z isselected from the group consisting of hydrogen, alkyl, aryl,functionalized alkyl, and functionalized aryl where the functionalgroup(s) may independently be one or more or the following: alkoxy,aryloxy, halogen, carboxylic acid, ketone, aldehyde, nitrate, cyano,isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide,disulfide, carbamate, silane, siloxane, phosphine, phosphate, andborate.
 2. The chelating carbene complex of claim 1, wherein thechelating carbene complex is prepared by a method comprising contactinga metathesis-active metal carbene complex of the formula X¹X²L¹L²M=CR¹R²with a beta-substituted styrene ligand precursor, wherein X¹, X², L¹,and M are as defined in claim 1; L² is any neutral electron donor, andwherein any of two or three of X¹, X², L¹, and L² may form amultidentate ligand; and R¹ and R² are each, independently, selectedfrom hydrogen or a substituent selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, alkylcarboxylate, arylcarboxylate,alkoxy, alkenyloxy, alkynyloxy, aryloxy, alkoxycarbonyl, alkylthio,alkylsulfonyl, alkylsulfinyl, or trialkylsilyl, wherein each of thesubstituents is substituted or unsubstituted, and wherein R¹ and R² maybe linked to form a substituted or unsubstituted cyclic group.
 3. Thechelating carbene complex of claim 1, wherein the ligand precursor is ofthe formula

wherein Y, Z, R⁵, R⁶, R⁷, and R⁸ are as defined in claim 1; n is 1, inthe case of a divalent heteroatom, or 2, in the case of a trivalentheteroatom; and R³ and R⁴ are each, independently, selected fromhydrogen or a substituent selected from the group consisting of alkyl,aryl, alkoxy, aryloxy, C₂-C₂₀ alkoxycarbonyl, or C₁-C₂₀ trialkylsilyl,wherein each of the substituents is substituted or unsubstituted.
 4. Amethod of preparing a metathesis-active metal chelating carbene complexcomprising a chelating carbene ligand, the method comprising contactinga metathesis-active metal carbene complex with a beta-substitutedstyrene ligand precursor to form the metathesis-active metal chelatingcarbene complex.
 5. The method of claim 4, wherein the metathesis-activemetal carbene complex is of the formula X¹X²L¹L²M=CR¹R², wherein X¹ andX² are each, independently, any anionic ligand; L¹ and L² are each,independently, any neutral electron donor, and wherein any of two orthree of X¹, X², L¹ and L² may form a multidentate ligand; M isruthenium or osmium; R¹ and R² are each, independently, selected fromhydrogen or a substituent selected from the group consisting of alkyl,alkenyl, alkynyl, aryl, alkylcarboxylate, arylcarboxylate, alkoxy,alkenyloxy, alkynyloxy, aryloxy, alkoxycarbonyl, alkylthio,alkylsulfonyl, alkylsulfinyl, or trialkylsilyl, wherein each of thesubstituents is substituted or unsubstituted, and wherein R¹ and R² maybe linked to form a substituted or unsubstituted cyclic group.
 6. Themethod of claim 4, wherein the ligand precursor is of the formula

wherein Y is a heteroatom selected from oxygen (O), sulfur (S), nitrogen(N), or phosphorus (P); Z is selected from hydrogen, alkyl, aryl,functionalized alkyl, or functionalized aryl where the functionalgroup(s) may independently be one or more or the following: alkoxy,aryloxy, halogen, carboxylic acid, ketone, aldehyde, nitrate, cyano,isocyanate, hydroxyl, ester, ether, amine, imine, amide, sulfide,disulfide, carbamate, silane, siloxane, phosphine, phosphate, or borate;n is 1, in the case of a divalent heteroatom, or 2, in the case of atrivalent heteroatom; R³ and R⁴ are each, independently, selected fromhydrogen or a substituent selected from the group consisting of alkyl,aryl, alkoxy, aryloxy, C₂-C₂₀ alkoxycarbonyl, or C₁-C₂₀ trialkylsilyl,wherein each of the substituents is substituted or unsubstituted; andR⁵, R⁶, R⁷, and R⁸ are each, independently, selected from the groupconsisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, alkoxy, alkenyloxy, aryloxy, alkoxycarbonyl, carbonyl,alkylamino, alkylthio, alkylsulfonyl, nitrile, nitro, alkylsulfinyl,trihaloalkyl, perfluoroalkyl, carboxylic acid, ketone, aldehyde,nitrate, cyano, isocyanate, hydroxyl, ester, ether, amine, imine, amide,sulfide, disulfide, sulfonate, carbamate, silane, siloxane, phosphine,phosphate, and borate, wherein any two of R⁵, R⁶, R⁷, and R⁸ may beindependently connected through hydrocarbon or functionalizedhydrocarbon groups forming an aliphatic or aromatic ring.